Peripheral blood leukocytes (PBL) from HTLV-III antibody (+) and (-) donors were tested for proliferative (3H) and cell-mediated lympholysis (CML) to influenza virus (S+X) and to HLA allogeneic cells (ALLO). Among antibody (+) donors, approximately 50% failed to respond to S+X, whereas all responded to ALLO, except patients in the critical stages of AIDS, who responded to neither type of immunogen. Using PBL from antibody (-) donors we demonstrated by cell fractionation techniques that S+X T cell responses are obliged to use CD4+ T cells, whereas ALLO responses can be generated by either CD4+ or CD4- T cells. Thus, the selective loss of S+X responses probably reflects the loss of CD4+ cells during AIDS development. Using the above approach, we have tested T cell functions in AIDS patients undergoing therapy with the thymidine analog AZT. Some patients undergoing AZT exhibited a restoration of T cell immune function. PBL from antibody (-) donors were infected with HTLV-III after stimulation with PHA or HLA alloantigens. PHA stimulated cells produced virus early but the cultures died within 2 weeks. In contrast, alloantigen stimulated cultures survived and produced virus for at least 40 days.